The studies are divided into two major categories: (1) the pharmacokinetics of TCA in the central nervous system, and (2) the cardiac effects of tricyclic antidepressants and their metabolities. The first group of studies is designed to provide a basic understanding of the effects of tricyclic antidepressants on cerebral capillary permeability both in terms of their cerebral extraction fraction (i.e. the fractional amount of the drug which enters the brain from the vascular compartment in a single transit time) as well as the extraction fractions of other psychoactive drugs. These permeability studies are the first step to elucidating factors influencing the CNS distribution of these agents. After the cerebral extraction fraction of TCA's are known, studies will be conducted to quantitate their regional distribution. From the data derived from these two studies, a mathemathical model of the kinetics of TCA distribution in the brain can be formulated. The second series of studies include animal and human projects which have potential clinical relevance to improving patient care and reducing morbidity due to tricyclic antidepressants. The studies are designed to (a) establish minimal plasma levels for cardiotoxic effects; (b) elucidate the mechanism of toxicity and relationship to age or underlying pre-existent cardiac dysfunction; (c) establish the relative potency of the parent compound and its major metabolites in terms of cardiotoxicity; (d) discover deleterious or advantageous drug interactions with regard to other cardiac agents; and (e) to test for a less cardiotoxic but still centrally active metabolite for clinical use or to attempt through structural alteration of the parent compound to produce a less cardiotoxic produrg. The results of these studies will be directly relevant to the treatment of patients with affective disorder and overdose patients. To summarize: the studies described in this application involve learning and applying techniques from both "basic" and "applied" sciences. This reflects my goal of becoming a specialist in clinical psychopharmacology which involves understanding clinical problems and improving patient care through knowledge derived from basic and applied research.